The present invention relates to compositions and methods for pulmonary administration of parathyroid hormone (parathormone, PTH) to mammalian hosts for the treatment of osteoporosis.
Human parathyroid hormone is an 84 amino acid protein (SEQ ID NO: 1) involved in calcium and phosphorus homeostasis and control of bone growth and density. Human PTH may be obtained through peptide synthesis or from genetically engineered yeast, bacterial or mammalian cell hosts. Human PTH is also commercially available from Bachem Inc., Bubendorf, Switzerland. Production of recombinant human parathyroid hormone is disclosed in EP-B0383751.
In mammals, the balance between bone formation, associated with the activity of osteoblasts, on one hand, and bone loss, associated with the activity of osteoclasts, on the other hand, is disturbed in several bone affecting diseases, such as osteoporosis. Parathyroid hormone has been shown to have a potential therapeutic role in osteoporosis. The anabolic actions of parathyroid hormone on bone are reviewed in Dempster et al. (1993) Endocrine Reviews, vol. 14, 690-709.
The N-terminal fragment of human PTH (PTH 1-34) was shown to have an anabolic effect on trabecular bone in involutional osteoporosis by Reeve et al. (1980) British Medical Journal, vol. 280, 1340-1344. However, the administration of a wild-type protein is to be preferred when possible, since this will ensure that all biological effects of the natural protein are exerted by the administered compound.
Polypeptide drugs such as PTH cannot be orally administered in effective doses, since they are rapidly degraded by enzymes in the gastrointestinal tract, and by the low pH in the stomach, before they can reach the bloodstream. Administration of PTH has generally been accomplished subcutaneously by injection. However, injection on a daily basis is inconvenient for the patient. Because of these disadvantages, there is a need for PTH in a form which is administrable other than by injection.
Pulmonary delivery of parathyroid hormone and N-terminal fragments thereof to rats is disclosed in WO 94/07514. When the N-terminal fragment consisting of amino acids 1-34 (PTH34) was administered to rats intratracheally (IT), the serum profile exhibited a peak after 15 minutes with activity diminishing rapidly thereafter. In contrast, the serum profile after IT administration of full-length PTH (ME84) exhibited a plateau which did not diminish significantly during the 90 minutes of the experiment. Since it is known that PTH is most effectively delivered to a patient in pulsatile fashion, i.e. serum concentrations should rise rapidly after administration and fall rapidly after a peak has been reached, it is concluded in the document WO 94/07514 that N-terminal fragments of PTH is preferred over the full-length protein for pulmonary delivery.
According to the present invention it has been shown that a pulsative plasma profile is obtained when full-length PTH as a dry powder aerosol is inhaled via an endotracheal tube by dogs. It has thus surprisingly been shown that pulmonary administration of full-length PTH, contrary to the conclusions expressed in the published patent application WO 94/07514, will be effective for stimulating bone formation and for the treatment of osteoporosis.